Now that Merck & Co.
has withdrawn rofecoxib (Vioxx) from the market because of increased risk of
heart attack and stroke, the attention is shifting to the other drugs of this
class.

Rofecoxib, celecoxib (Celebrex),
and valdecoxib (Bextra) are a subclass of nonsteroidal anti-inflammatory drugs
(NSAIDs) that selectively block the enzyme COX-2 (cyclooxygenase-2). When Merck
announced the rofecoxib withdrawal, it said that its study results were not
necessarily applicable to others in the COX-2 inhibitor class.

A rheumatologist who says
rofecoxib has benefited many of his patients is not too concerned about the
cardiovascular risk of the other two drugs — at this point. "I think we should
go by the data that we have," says Hayes Wilson, MD, a rheumatologist
at Piedmont Hospital in Atlanta and a medical adviser for the Arthritis Foundation.
"Vioxx was pulled because they got new prospective data that said that it was
trending in the wrong direction for heart disease. But the data for Celebrex
and Bextra are that it is safe. Any medication that is strong enough to help
you is strong enough to potentially give you a side effect. Any time you take
a medication, it is a calculated risk."

The other COX-2 inhibitors,
though, are a concern for Gordon J. Vanscoy, PharmD, CACP, MBA, assistant
dean for managed care and associate professor of pharmaceutical sciences at
the University of Pittsburgh School of Pharmacy. He also is chairman and chief
executive officer of University Pharmacotherapy Associates in Monroeville, PA.
"I definitely think there needs to be more studies."

It is not known if the
problem is a class effect, he says. Are the side effects inevitable after the
broad use of the COX-2 products, or are they truly specific to the chemical
structure of rofecoxib?

Vanscoy foresees more clinical
monitoring of patients on celecoxib and valdecoxib to see if the patients experience
any of the same serious cardiovascular side effects as those taking rofecoxib.
"I think there is an obligation on behalf of the other manufacturers to ensure
that we don’t have an analogous situation."

The call to arms

Other physicians are alarmed
about the rofecoxib withdrawal. The New England Journal of Medicine published
two editorials from such physicians; the editorials were published on its web
site on Oct. 6 and will appear in the Oct. 21 printed issue.

One of the editorials calls
for further investigations of the COX-2 class. The APPROVe (Adenomatous Polyp
Prevention on VIOXX) trial, the results of which led Merck to pull rofecoxib
from the market, has shifted the burden of proof, says Garret A. FitzGerald,
MD, professor and chair of the department of pharmacology at the University
of Pennsylvania School of Medicine in Philadelphia. "[It] now rests with those
who claim that this is a problem for rofecoxib alone and does not extend to
other coxibs.

"We now have clear evidence
of an increase in cardiovascular risk that revealed itself in a manner consistent
with a mechanistic explanation that extends to all the coxibs. It seems to be
time for the FDA urgently to adjust its guidance to patients and doctors to
reflect this new reality."

It is essential to determine
whether the cardiovascular risk is or is not a class effect, FitzGerald says.
"We must remember that the absence of evidence is not the evidence of absence."

The withdrawal is a warning
to the class, although [the risks] may not hold across the class, Vanscoy says.
"You are better off being safe than sorry."

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